Acta Neuropathologica

, Volume 120, Issue 5, pp 641–649

Glucocerebrosidase is present in α-synuclein inclusions in Lewy body disorders

  • Ozlem Goker-Alpan
  • Barbara K. Stubblefield
  • Benoit I. Giasson
  • Ellen Sidransky
Original Paper

DOI: 10.1007/s00401-010-0741-7

Cite this article as:
Goker-Alpan, O., Stubblefield, B.K., Giasson, B.I. et al. Acta Neuropathol (2010) 120: 641. doi:10.1007/s00401-010-0741-7

Abstract

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase, known to cause Gaucher disease (GD), are a risk factor for the development of Parkinson disease (PD) and related disorders. This association is based on the concurrence of parkinsonism and GD, the identification of glucocerebrosidase mutations in cohorts with PD from centers around the world, and neuropathologic findings. The contribution of glucocerebrosidase to the development of parkinsonian pathology was explored by studying seven brain samples from subjects carrying glucocerebrosidase mutations with pathologic diagnoses of PD and/or Lewy body dementia. Three individuals had GD and four were heterozygous for glucocerebrosidase mutations. All cases had no known family history of PD and the mean age of disease onset was 59 years (range 42–77). Immunofluorescence studies on brain tissue samples from patients with parkinsonism associated with glucocerebrosidase mutations showed that glucocerebrosidase was present in 32–90% of Lewy bodies (mean 75%), some ubiquitinated and others non-ubiquitinated. In samples from seven subjects without mutations, <10% of Lewy bodies were glucocerebrosidase positive (mean 4%). This data demonstrates that glucocerebrosidase can be an important component of α-synuclein-positive pathological inclusions. Unraveling the role of mutant glucocerebrosidase in the development of this pathology will further our understanding of the lysosomal pathways that likely contribute to the formation and/or clearance of these protein aggregates.

Keywords

Glucocerebrosidaseα-SynucleinParkinsonismLewy body dementia

Supplementary material

401_2010_741_MOESM1_ESM.eps (18 mb)
Figure S1 Representative sections from cases 1 and 4 (also shown in Figure 1) were stainedwith monoclonal anti-GC antibody (Abnova, Taipei, Taiwan) and sheep polyclonal anti-α-synuclein (1:400) (ABR, Rockford, IL). Immunofluorescent staining was followed by SudanBlack staining to quench autofluorescence [24]. Sudan Black did not affect the distribution orintensity of GC staining in LBs and LNs in subjects with GBA mutations. LAMP-1 positive,perikaryal amorphous inclusions still persisted after Sudan quenching. LAMP1 (purple), GC(green) and α-synuclein (red). DAPI (blue) was used as a nuclear counterstain. Scale bar =10microns (EPS 18,440 KB)
401_2010_741_MOESM2_ESM.eps (6 mb)
Figure S2Immunofluorescent staining using rabbit polyclonal anti-GC (R386) antibody. BothGC positive and negative (arrow) α-synuclein pathology are present in the same field. GC (red)and α-synuclein (green). DAPI (blue) was used as a nuclear counterstain. Scale bar=10 microns (EPS 6,173 KB)

Copyright information

© US Government 2010

Authors and Affiliations

  • Ozlem Goker-Alpan
    • 1
  • Barbara K. Stubblefield
    • 1
  • Benoit I. Giasson
    • 2
  • Ellen Sidransky
    • 1
  1. 1.Section on Molecular Neurogenetics, Medical Genetics BranchNHGRI, National Institutes of HealthBethesdaUSA
  2. 2.Department of PharmacologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA